Luzelena Caro

Pitavastatin is a more sensitive and selective organic anion‐transporting polypeptide 1B clinical probe than rosuvastatin

AIMS Rosuvastatin and pitavastatin have been proposed as probe substrates for the organic anion-transporting polypeptide (OATP) 1B, but clinical data on their relative sensitivity and selectivity to OATP1B inhibitors are lacking. A clinical study was therefore conducted to determine their relative suitability as OATP1B probes using single oral (PO) and intravenous (IV) doses of the OATP1B inhibitor rifampicin, accompanied by a comprehensive in vitro assessment of rifampicin inhibitory potential on statin transporters. METHODS The clinical study comprised of two separate panels of eight healthy subjects. In each panel, subjects were randomized to receive a single oral dose of rosuvastatin (5 mg) or pitavastatin (1 mg) administered alone, concomitantly with rifampicin (600 mg) PO or IV. The in vitro transporter studies were performed using hepatocytes and recombinant expression systems. RESULTS Rifampicin markedly increased exposures of both statins, with greater differential increases after PO vs. IV rifampicin only for rosuvastatin. The magnitudes of the increases in area under the plasma concentration-time curve were 5.7- and 7.6-fold for pitavastatin and 4.4- and 3.3-fold for rosuvastatin, after PO and IV rifampicin, respectively. In vitro studies showed that rifampicin was an inhibitor of OATP1B1 and OATP1B3, breast cancer resistance protein and multidrug resistance protein 2, but not of organic anion transporter 3. CONCLUSIONS The results indicate that pitavastatin is a more sensitive and selective and thus preferred clinical OATP1B probe substrate than rosuvastatin, and that a single IV dose of rifampicin is a more selective OATP1B inhibitor than a PO dose.

Niacin Lipid Efficacy Is Independent of Both the Niacin Receptor GPR109A and Free Fatty Acid Suppression

GPR109A is not the target mediating niacin’s lipid efficacy and the free fatty acid hypothesis does not explain niacin’s mechanism of action. Breaking Free of the “FFA Hypothesis” Free fatty acids (FFAs) appear in the blood plasma after a meal. Niacin—a vitamin that helps to regulate lipid levels in the body—is given to patients to reduce the amount of FFAs. It also works to raise “good” cholesterol [high-density lipoprotein (HDL)] and lower both “bad” cholesterol [low-density lipoprotein (LDL)] and triglycerides. The “FFA hypothesis” suggests that niacin works to exert these beneficial lipid effects by limiting the amount of FFAs available to synthesize triglycerides. Lauring, Taggart, and colleagues now challenge this long-standing theory. In studies in mice and humans, the authors debunk the hypothesis, showing that the effect on HDL, LDL, and triglycerides is not directly linked to FFAs. To study the lipid-modifying effects of niacin (nicotinic acid), Lauring et al. used a genetic, humanized mouse model lacking the LDL receptor. In these animals, niacin increased HDL cholesterol levels, as expected. Lack of GPR109A in these animals blocked the anti-lipolytic effect of nicotinic acid on FFAs but had no effect on drug-related changes in plasma HDL and LDL cholesterol or triglyceride levels. Treatment of the mice with a GPR109A agonist, MK-1903, also caused an anti-lipolytic effect but did not affect levels of triglyceride or LDL and HDL cholesterol. Together, these in vivo preclinical studies suggest that niacin works to lower FFAs through GPR109A but has an independent mechanism of action on other lipids. The authors addressed the role of GPR109A in humans by testing the effects of MK-1903 and of another synthetic GPR109A agonist in clinical trials. Both agonists affected FFA lipolysis but had only minor effects on HDL cholesterol and triglyceride levels in patients, thus mirroring results seen in animals and showing that niacin works independently of GPR109A to modify dyslipidemia. The studies by Lauring et al. point to a new, yet-uncovered mechanism of action for niacin’s beneficial effects on lipids in the blood. Despite overturning the FFA hypothesis and potentially redirecting drug development away from GPR109A agonists, niacin could still be useful for treating other diseases in patients, including atherosclerosis and inflammation, where GPR109A plays a major role in cell signaling. Nicotinic acid (niacin) induces beneficial changes in serum lipoproteins and has been associated with beneficial cardiovascular effects. Niacin reduces low-density lipoprotein, increases high-density lipoprotein, and decreases triglycerides. It is well established that activation of the seven-transmembrane Gi-coupled receptor GPR109A on Langerhans cells results in release of prostaglandin D2, which mediates the well-known flushing side effect of niacin. Niacin activation of GPR109A on adipocytes also mediates the transient reduction of plasma free fatty acid (FFA) levels characteristic of niacin, which has been long hypothesized to be the mechanism underlying the changes in the serum lipid profile. We tested this “FFA hypothesis” and the hypothesis that niacin lipid efficacy is mediated via GPR109A by dosing mice lacking GPR109A with niacin and testing two novel, full GPR109A agonists, MK-1903 and SCH900271, in three human clinical trials. In mice, the absence of GPR109A had no effect on niacin’s lipid efficacy despite complete abrogation of the anti-lipolytic effect. Both MK-1903 and SCH900271 lowered FFAs acutely in humans; however, neither had the expected effects on serum lipids. Chronic FFA suppression was not sustainable via GPR109A agonism with niacin, MK-1903, or SCH900271. We conclude that the GPR109A receptor does not mediate niacin’s lipid efficacy, challenging the long-standing FFA hypothesis.

Vaniprevir With Pegylated Interferon Alpha-2a and Ribavirin in Treatment-Naive Patients With Chronic Hepatitis C: A Randomized Phase II Study

Vaniprevir (MK‐7009) is a macrocyclic hepatitis C virus (HCV) nonstructural protein 3/4A protease inhibitor. The aim of the present phase II study was to examine virologic response rates with vaniprevir in combination with pegylated interferon alpha‐2a (Peg‐IFN‐α‐2a) plus ribavirin (RBV). In this double‐blind, placebo‐controlled, dose‐ranging study, treatment‐naïve patients with HCV genotype 1 infection (n = 94) were randomized to receive open‐label Peg‐IFN‐α‐2a (180 μg/week) and RBV (1,000‐1,200 mg/day) in combination with blinded placebo or vaniprevir (300 mg twice‐daily [BID], 600 mg BID, 600 mg once‐daily [QD], or 800 mg QD) for 28 days, then open‐label Peg‐IFN‐α‐2a and RBV for an additional 44 weeks. The primary efficacy endpoint was rapid viral response (RVR), defined as undetectable plasma HCV RNA at week 4. Across all doses, vaniprevir was associated with a rapid two‐phase decline in viral load, with HCV RNA levels approximately 3log10 IU/mL lower in vaniprevir‐treated patients, compared to placebo recipients. Rates of RVR were significantly higher in each of the vaniprevir dose groups, compared to the control regimen (68.8%‐83.3% versus 5.6%; P < 0.001 for all comparisons). There were numerically higher, but not statistically significant, early and sustained virologic response rates with vaniprevir, as compared to placebo. Resistance profile was predictable, with variants at R155 and D168 detected in a small number of patients. No relationship between interleukin‐28B genotype and treatment outcomes was demonstrated in this study. The incidence of adverse events was generally comparable between vaniprevir and placebo recipients; however, vomiting appeared to be more common at higher vaniprevir doses. Conclusion: Vaniprevir is a potent HCV protease inhibitor with a predictable resistance profile and favorable safety profile that is suitable for QD or BID administration. (HEPATOLOGY 2012;56:884–893)

The Combination of MK-5172, Peginterferon, and Ribavirin Is Effective in Treatment-Naive Patients With Hepatitis C Virus Genotype 1 Infection Without Cirrhosis

BACKGROUND & AIMS MK-5172 is an inhibitor of the hepatitis C virus (HCV) nonstructural protein 3/4A protease; MK-5172 is taken once daily and has a higher potency and barrier to resistance than licensed protease inhibitors. We investigated the efficacy and tolerability of MK-5172 with peginterferon and ribavirin (PR) in treatment-naive patients with chronic HCV genotype 1 infection without cirrhosis. METHODS We performed a multicenter, double-blind, randomized, active-controlled, dose-ranging, response-guided therapy study. A total of 332 patients received MK-5172 (100, 200, 400, or 800 mg) once daily for 12 weeks in combination with PR. Patients in the MK-5172 groups received PR for an additional 12 or 36 weeks, based on response at week 4. Patients in the control group (n = 66) received a combination of boceprevir and PR, dosed in accordance with boceprevirs US product circular. RESULTS At 24 weeks after the end of therapy, sustained virologic responses were achieved in 89%, 93%, 91%, and 86% of the patients in the groups given the combination of PR and MK-5172 (100, 200, 400, or 800 mg), respectively, vs 61% of controls. In the MK-5172 group receiving 100 mg, 91% of patients had undetectable levels of HCV RNA at week 4 and qualified for the short duration of therapy. The combination of MK-5172 and PR generally was well tolerated. Transient increases in transaminase levels were noted in the MK-5172 groups given 400 and 800 mg, at higher frequencies than in the MK-5172 groups given 100 or 200 mg, or control groups. CONCLUSIONS Once-daily MK-5172 (100 mg) with PR for 24 or 48 weeks was highly effective and well tolerated among treatment-naive patients with HCV genotype 1 infection without cirrhosis. Studies are underway to evaluate interferon-free MK-5172-based regimens. ClinicalTrials.gov number: NCT01353911.

(1aR,5aR)1a,3,5,5a-Tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (MK-1903): a potent GPR109a agonist that lowers free fatty acids in humans.

G-protein coupled receptor (GPCR) GPR109a is a molecular target for nicotinic acid and is expressed in adipocytes, spleen, and immune cells. Nicotinic acid has long been used for the treatment of dyslipidemia due to its capacity to positively affect serum lipids to a greater extent than other currently marketed drugs. We report a series of tricyclic pyrazole carboxylic acids that are potent and selective agonists of GPR109a. Compound R,R-19a (MK-1903) was advanced through preclinical studies, was well tolerated, and presented no apparent safety concerns. Compound R,R-19a was advanced into a phase 1 clinical trial and produced a robust decrease in plasma free fatty acids. On the basis of these results, R,R-19a was evaluated in a phase 2 study in humans. Because R,R-19a produced only a weak effect on serum lipids as compared with niacin, we conclude that the beneficial effects of niacin are most likely the result of an undefined GPR109a independent pathway.

Characterization of vaniprevir, a hepatitis C virus NS3/4A protease inhibitor, in patients with HCV genotype 1 infection: Safety, antiviral activity, resistance, and pharmacokinetics

Vaniprevir is a competitive inhibitor of the hepatitis C virus (HCV) NS3/4A protease that has potent anti-HCV activity in preclinical models. This placebo-controlled dose-ranging study assessed the safety, tolerability, and antiviral efficacy of vaniprevir monotherapy in patients with genotype 1 chronic HCV infection. Treatment-naive and treatment-experienced non-cirrhotic adult patients with baseline HCV RNA >10(6)IU/ml were randomized to receive placebo or vaniprevir at doses of 125 mg qd, 600 mg qd, 25mg bid, 75 mg bid, 250 mg bid, 500 mg bid, and 700 mg bid for 8 days. Forty patients (82.5% male, 75% genotype 1a) received at least one dose of placebo or vaniprevir. After 1 week of vaniprevir, the decrease in HCV RNA from baseline ranged from 1.8 to 4.6 log₁₀IU/ml across all treatment groups, and there was a greater than dose-proportional increase in vaniprevir exposure at doses above 75 mg bid. The most commonly reported drug-related adverse events (AEs) were diarrhea (n=5) and nausea (n=5). No pattern of laboratory or ECG abnormalities was observed, all AEs resolved during the study, and there were no discontinuations due to AEs. No serious AEs were reported. Resistance-associated amino acid variants were identified at positions R155 and D168 in patients infected with genotype 1a virus. Vaniprevir monotherapy demonstrated potent antiviral activity in patients with chronic genotype 1 HCV infection, and was generally well tolerated with no serious AEs or discontinuations due to AEs. Further development of vaniprevir, including studies in combination with other anti-HCV agents, is ongoing.

Pharmacokinetics of oral dexamethasone and midazolam when administered with single-dose intravenous 150 mg fosaprepitant in healthy adult subjects.

Aprepitant or its prodrug fosaprepitant, in combination with a corticosteroid and a 5‐HT3 receptor antagonist, are used to prevent chemotherapy‐induced nausea and vomiting. This study evaluated the effect of fosaprepitant 150 mg on CYP3A4 metabolism. Fosaprepitant 150 mg has been submitted to regulatory agencies for consideration of approval as a single‐day alternative to the 3‐day oral aprepitant antiemetic regimen currently marketed. Part 1 of the study evaluated the drug interaction between fosaprepitant 150 mg and oral dexamethasone (8 mg daily for 3 days). Part 2 of the study evaluated the drug interaction between fosaprepitant 150 mg and oral midazolam (2 mg on days 1 and 4). Thirteen subjects were enrolled in part 1 and 10 in part 2. For dexamethasone, fosaprepitant increased the area under the plasma concentration—time curve from 0 to 24 hours by approximately 2.0‐fold on days 1 and 2 and to a lesser extent (∼1.2‐fold) on day 3. Similarly, for midazolam, fosaprepitant increased the area under the plasma concentration—time curve from 0 hours to infinity by approximately 1.8‐fold on day 1 but had no effect on midazolam pharmacokinetics on day 4. Fosaprepitant 150 mg is a weak inhibitor of CYP3A4. Oral dexamethasone doses on days 1 and 2 should be reduced by approximately 50% when coadministered with intravenous fosaprepitant 150 mg on day 1.

No Pharmacokinetic Interaction Between the Hepatitis C Virus Inhibitors Elbasvir/Grazoprevir and Famotidine or Pantoprazole

Use of agents to suppress gastric acid secretion is common among patients with hepatitis C virus (HCV) infection. The aims of this open‐label, three‐period, fixed‐sequence study were to evaluate the effect of famotidine and pantoprazole on the pharmacokinetics and safety of elbasvir/grazoprevir fixed‐dose combination (FDC) in 16 healthy subjects. Elbasvir and grazoprevir each exhibited similar pharmacokinetics following single‐dose administration of elbasvir/grazoprevir with or without famotidine or pantoprazole. Geometric mean ratios (GMRs) of grazoprevir AUC(0,∞), Cmax, and C24 (elbasvir/grazoprevir + famotidine or elbasvir/grazoprevir + pantoprazole vs. elbasvir/grazoprevir) ranged from 0.89–1.17. Similarly, GMRs of elbasvir AUC(0,∞), Cmax, and C24 (elbasvir/grazoprevir + famotidine or elbasvir/grazoprevir + pantoprazole vs. elbasvir/grazoprevir) ranged from 1.02–1.11. These results indicate that gastric acid‐reducing agents do not modify the pharmacokinetics of elbasvir or grazoprevir in a clinically relevant manner and may be coadministered with elbasvir/grazoprevir in HCV‐infected patients without restriction.

Effect of hepatic impairment on the pharmacokinetics of grazoprevir, a hepatitis C virus protease inhibitor

ABSTRACT Grazoprevir (GZR) plus elbasvir is an approved treatment for chronic infection with hepatitis C virus (HCV) genotype 1 or 4. HCV infection complications include liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The objective of this study was to evaluate the pharmacokinetics and safety of multiple-dose GZR (200, 100, or 50 mg) in non-HCV participants with mild, moderate, or severe hepatic impairment (HI), respectively, and in healthy matched controls (protocol MK-5172_p013; Merck & Co., Inc., Kenilworth, NJ). Participants with mild, moderate, or severe HI and controls (aged 18 to 65 years) matched for race, age, sex, and body mass index were enrolled in a 3-part, open-label, sequential-panel pharmacokinetic study. Participants received oral doses of GZR 200 mg (two 100-mg tablets), 100 mg (one 100-mg tablet), or 50 mg (two 25-mg tablets) once daily for 10 days. A total of 50 participants were enrolled: 8 with mild HI, 9 with moderate HI, 8 with severe HI, and a corresponding number of healthy matched controls for each hepatic cohort. Participants with HI demonstrated higher GZR exposure than healthy matched controls and showed an increase in exposure with increasing HI severity. The steady-state GZR AUC0–24 (area under the concentration-time curve from 0 to 24 h) for participants with mild, moderate, or severe HI was ≈2-, ≈5-, or ≈12-fold higher, respectively, than that for healthy matched controls. GZR was generally well tolerated in participants with HI. No dose adjustment is required for GZR in people with HCV with mild HI. GZR is contraindicated for those with moderate or severe HI (Child-Pugh class B or C), since they may have significantly increased GZR exposures that may lead to an increased risk of transaminase elevation.

P0910 : No evidence of pharmacokinetic drug–drug interaction in healthy subjects between coadministered grazoprevir (MK-5172)/elbasvir (MK-8742) and sofosbuvir

Background and aims: Grazoprevir (MK-5172), a potent inhibitor of the hepatitis C virus (HCV) NS3/4A protease, and elbasvir (MK-8742), a potent inhibitor of the HCV NS5A replication complex, are being developed evaluated the effect of grazoprevir and elbasvir on the pharmacokinetics of sofosbuvir (SOF), an HCV NS5B inhibitor, when coadministered in healthy subjects. Methods: grazoprevir and elbasvir on the pharmacokinetics of a single oral dose of SOF. Sixteen (16) healthy adult male and female subjects were enrolled. In Period 1, subjects received a single oral 400-mg dose of SOF. Following an 8-day washout period, multiple oral doses of 200 mg grazoprevir and 50 mg elbasvir were coadministered QD from Days 1 to 15, inclusive, in Period 2. On Day 11, a single oral dose of SOF was coadministered with the dose of grazoprevir and elbasvir. Plasma pharmacokinetic parameters of SOF and its principal nucleoside metabolite (GS-331007) were measured in Period 1 and following the dose on Day 11 in Period 2. Results: (90% CIs)] for plasma SOF AUC0-∞ and Cmax were 2.43 [2.12, 2.79] and 2.27 [1.72, 2.99], respectively. These changes in SOF exposure are not considered to be clinically meaningful based on the safety margins of SOF. The GMRs [90% CIs] for plasma GS-331007 AUC0-∞ and Cmax for the same comparison were 1.13 [1.05, 1.21] and 0.87 [0.78, 0.96], respectively. These changes in GS-331007 exposure are not considered to be clinically meaningful. Coadministration of SOF, grazoprevir, and elbasvir was generally well tolerated. Conclusions: Multiple-dose administration of 200 mg grazoprevir and 50 mg elbasvir daily with a single dose of SOF was generally well tolerated by healthy subjects in this study. Coadministration of elbasvir and grazoprevir with SOF had no clinically meaningful effect on the pharmacokinetics of SOF and its metabolite GS-331007. Taken together with the lack of potential for SOF to perpetrate a drug-drug interaction on grazoprevir or elbasvir, these results suggest that SOF, grazoprevir, and elbasvir may be coadministered without dose adjustment.